1. Field Of the Invention
This invention concerns a diagnostic test useful for prenatal identification of Down syndrome and mental retardation and a gene therapy for correction and treatment thereof. In particular, this invention concerns identification of DYRK gene involved in the ability to learn. The invention further concerns a method for diagnosing Down's syndrome and mental retardation and an assay therefor, a method for gene therapy of Down's syndrome and a pharmaceutical composition for treatment of Down's syndrome mental retardation.
2. Background Art and Related Disclosures
Down syndrome occurs in about one out of every 800 newborns, with the incidence increasing markedly in the offspring of women over 35. Affecting an estimated one million Americans, it is the leading genetic cause of mental retardation and is associated with a shorter than average life expectancy. Other symptoms are heart and intestinal defects, problems with the immune and endocrine systems, and raft of tissue and skeletal deformities.
Individuals with Down syndrome carry a complete extra copy of chromosome 21 in all of their cells, giving each cell a total of 47 chromosomes rather than the normal 46. For this reason, the condition is also known as "Trisomy 21". There are, however, rare forms of Down syndrome in which only part of chromosome 21 is present in triplicate.
The existence of these rare forms of Down syndrome suggests that the condition may be due to a limited number of genes and led to development of the current invention and to creation of a special series of transgenic mice containing different adjacent segments of human chromosome 21.
Up to date, there is no available treatment of the Down's syndrome mental retardation and learning disability and for correction of this genetic defect.
Recently, with the advent of biotechnology, more and more genetic tools have been developed leading to a new way of treatment of the genetic diseases by gene therapy. To this end, complex trait analysis is assuming increasing importance in understanding mammalian biology. New mapping reagents, such as polymorphic markers distributed throughout the genome described in Nature, 380: 152 (1996) and Prog. Clin. Biol. Res., 384:1 (1993), have assisted in the quantitation of the number of genes contributing to such traits and in their localization. Despite these advances, the multi-factorial nature of these traits means that ultimate identification of the responsible genes will be extremely difficult.
Down syndrome can be regarded as a complex trait, as it is likely that numerous genes contribute to the phenotype (PNAS (USA), 91:4997 (1994)). The syndrome results in a variety of distinct phenotypes (PNAS (USA), 86:5958 (1989) and importantly, is the leading genetic cause of mental retardation in humans, with over 1 million affected in the United States.
Although controversial, there is evidence that an extra dose of one region of chromosome 21 at 21q22.2 may be particularly important in the pathogenesis of the syndrome (ibid). These studies, together with analogous investigations employing mice described in Nature Genet., 11:177 (1995), indicate that the 21q22.2 region, or the region of mouse chromosome 16 syntenic with human chromosome 21, contains genes that affect learning and memory when their dose is increased by a modest amount. These analyses, however, fail to map individual loci contributing to the behavioral abnormalities.
As an approach to fine mapping and identification of loci from 21q22.2 region contributing to learning impairment and behavior observed with Down syndrome when present in an extra dose, the current invention describes multiple lines of transgenic mice containing several contiguous YACs from 21q22.2. This panel of low copy number YAC transgenic is referred to as an in vivo library, because in total a significant segment of about 4% of human chromosome 21 is propagated in vivo, using the mouse as a host and Identifying the genetic material by testing the mouse learning ability and behavior. Using this in vivo library, loci affecting learning and memory from the 21q22.2 region of the human genome could thus be identified in phenotypic screens employing functional assays for behavior.
It is, therefore, a primary objective of this invention to identify loci from chromosome 21q22.2, responsible for Down syndrome, using the Down syndrome as a model for complex trait analysis and utilizing this identification for diagnostic and therapeutic purposes. It is also another objective to determine under which conditions an extra dose of loci from chromosome 21q22.2, when present, contribute to learning abnormalities.
All patents, patent applications and manuscript disclosed in this specification are hereby incorporated by reference.